Rheumatoid arthritis (RA), a chronic inflammatory disease affecting 1% of the population, is associated with heightened mortality predominantly due to accelerated atherosclerosis. Systemic inflammation has powerful effects on endothelial function and contributes to increased atherosclerosis and plaque rupture. Therefore, the ideal therapy for a disease like RA is one in which multiple pathologic processes are addressed by reducing inflammation and preventing or reversing abnormalities of endothelial function. Peroxisome proliferator-activated receptor-y (PPAR-y) agonists are drugs with profound pleitropic effects on the vasculature and on inflammatory cascades which make them very attractive therapeutic options for both atherosclerosis/endothelial dysfunction prevention and for treatment of inflammation in RA. The primary goal of the proposed project is to evaluate the efficacy of pioglitazone, a PPAR-y agonist, in improving markers of endothelial dysfunction and atherosclerosis risk in RA. As a secondary aim-point, we will evaluate the efficacy of pioglitazone in improving RA disease activity and markers of inflammation. The proposed clinical trial will be a randomized, placebo controlled double blinded, cross-over study of 144 RA patients, randomized to receive pioglitazone or placebo. Patients will be treated for 3 months with either pioglitazone or placebo, undergo a washout period of 8 weeks, and then undergo crossover to the other arm for an additional 3 months. The role of pioglitazone on endothelial biology and function will be studied by: 1) Brachial artery flow mediated dilatation and nitroglycerin-mediated dilatation, validated surrogate markers of endotheliumdependent and independent function, respectively, before and after therapy with pioglitazone; 2) Arterial compliance, as arterial stiffness is an important predictor of cardiovascular damage, before and after treatment with pioglitazone; 3) Examination of specific serum biomarkers of endothelial damage and cardiovascular risk, before and after treatment with pioglitazone. The effect on inflammation and RA disease activity will be assessed, by: 1) The Disease Activity Scale (DAS-28); and 2) Studying markers of systemic inflammation and inflammatory cytokines. If therapy with pioglitazone improves endothelial function and decreases inflammation in RA it may provide a safe, effective, relatively inexpensive adjuvant therapy both for the prevention of premature atherosclerosis and the persistence of inflammation in this disease. This study will also shed further light on the biology of endothelial cell injury in RA. [unreadable] [unreadable] [unreadable]